Several polypeptides found in the thymus gland have been implicated as playing roles in the development and maintenance of immunological competence in animals, including human beings. Some of these polypeptides have been shown to stimulate the maturation, differentiation and function of T-cells. For example, a heat-stable fraction isolated from calf thymus extracts, designated as Thymosin fraction 5, has been shown to reconstitute immune functions in thymic-deprived or immunodepressed individuals. Several peptides have been isolated from Thymosin fraction 5, such as Thymosin alpha.sub.1 (28 amino acids, U.S. Pat. No. 4,079,127), Thymosin beta.sub.4 (44 amino acids, Low et al., PNAS, 78,1162-1166 (1981)), Thymosin beta.sub.8 (39 amino acids, U.S. Pat. No. 4,389,343) and Thymosin beta.sub.9 (41 amino acids, U.S. Pat. No. 4,389,343). However, practical administration of such polypeptides is expensive due to the relatively low yield and complexity of isolation and/or manufacture of such long chain polypeptides. Most importantly, in some cases, these polypeptides produce side reactions in patients.
The present invention is based in part on the discovery that a dipeptide, L-Ile-L-Trp, including linear or cyclic forms of this dipeptide or polymers thereof, exhibit a broad range of efficacy for prevention and treatment of opportunistic infections in immunodepressed states, and for therapeutically effective treatment of immunodeficient states. This is believed to be highly unexpected for such a relatively small compound to exhibit such a broad range of activity. Furthermore, we have not found any significant side effects from the use of t:he dipeptide according to the present invention. Due to its simple nature, the dipeptide is rather inexpensive to manufacture.
As used herein, the terms "immunomodulator" and "immunomodulating" encompass the activity of enhancing or restoring the subject's immune system, as evidenced by measurable blood parameters and/or the patient's improved ability to combat infection or disease, and the ability to heal tissue. Hence, immunomodulation encompasses improvement of the immune system due to an immunodeficient state (for example, caused by removal of the thymus), and/or an immunodepressed state (for example, caused by exposure to radiation). Furthermore, the present invention provides for modulation of the immune system by lowering blood parameters and other indicia of the immune state if these indicia are abnormally elevated. The present invention encompasses the therapeutic method of treating the immunodeficient, immunodepressed or elevated immune state per se, thus providing prophylaxis against infection and disease, as well as a treatment of infection, disease or wound indirectly by enhancing the immune system.
It is therefore an object of the present invention to provide pharmaceutical compositions of the L-Ile-L-Trp dipeptide which have broad immunomodulating activity, as well as activity for other uses such as treatment of infections, disease and wounds (burns, frost bites, and the like), enhancement of metabolic processes, and many other uses.
It is an object of the present invention to provide therapeutic methods for treatment of immunodepressed and immunodeficient states.
It is yet another object of the present invention to provide methods for preventing and treating opportunistic infections in immunodeficient and immunodepressed states.
These and other objects will be apparent from the following description and appended claims.